Project Summary/Abstract Genetic testing is an integral part of the evaluation of patients with disorders of sex development (DSD), and the arrival of whole-exome sequencing in the clinic has the potential to greatly facilitate the diagnosis of DSD. However, several barriers prevent this approach from reaching its full clinical potential. Our incomplete knowledge of both the genes and the specific variants associated with DSD impairs our ability to recognize pathogenic mutations. Despite growing evidence that mutations in DSD genes can produce a broad spectrum of phenotypes, current guidelines recommend restricting the evaluation for DSD to severe cases of undervirilization or overvirilization, resulting in potential missed opportunities both for diagnosis and for understanding the full range of genotype-phenotype associations for DSD genes. Psychosocial outcomes of genetic testing have been understudied in patients and families affected by DSD, and while whole-exome sequencing has the potential to provide valuable diagnostic information, it may not produce a clear diagnosis in many cases and has the potential to add to anxiety and stress. This project will address these barriers by applying and evaluating whole-exome sequencing in subjects with DSD and related conditions. Aim 1 of this project uses whole-exome sequencing both in patients with ?textbook? presentations of DSD as well as in patients with an expanded spectrum of presentations of apparent undervirilization (such as hypospadias with or without bifid scrotum) or apparent overvirilization (such as isolated clitoromegaly). Aim 2 of this project assesses the impact of returning genetic testing results on parents using a series of validated measures, including assessments of anxiety, stress, expectations, and utility. These studies will provide essential information to direct the use of whole-exome sequencing in the clinical care of patients with broad range of conditions that result in apparent over/undervirilization.